Our previous studies have revealed potent synthetic activities (e.g., PPi:-, ATP:-, and carbamyl-P:glucose phosphotransferase) catalyzed by D-glucose-6-P phosphohydrolase (EC 3.1.3.9). These activities intrinsically exceed both this enzyme's capacity for glucose-6-P hydrolysis and the combined phosphorylative action of hepatic hexokinase plus glucokinase. 1. A major emphasis will now be placed on assessing metabolic functions which these synthetic activities may play in living cells, especially as they may complement hexokinase and glucokinase in glucose phosphorylation. The possibility of kinase-specific metabolic channeling will be considered. 2. Roles for both phosphotransferase and phosphohydrolase activities of hepatic glucose-6-phosphatase in control of ambient blood glucose levels normally and under various perturbed conditions will be emplored. Perfused rat and avian livers and isolated hepatic parenchymal cells will be employed, and rates of glucose phosphorylation directly attributable to the subject phosphotransferases will be measured by 3H-release from 2-3H-D-glucose. Alterations in blood glucose levels through differential readjustment ("retuning") of rates of enzymic glucose phosphorylation and glucose-6-P hydrolysis will be considered in various species under normal conditions, in diabetes, fasting, ageing, congenital hyper- and hypoglycemia, and hormonally, nutritionally, and pharmacologically altered states. 3. The multifunctional enzyme newly demonstrated in brain, pancreas, adrenals, testes, and lung will be further studied with respect to comparative catalytic characteristics; hormonally, nutritionally, and chemotherapeutically induced responses; and probable metabolic roles. Also included will be 4) extensions of distribution studies, 5) studies of activity-discriminant control through membrane-enzyme interactions; the effects of the hormones somatostatin, glucagon, and insulin; and Cu 2 ion and other divalent cations, 6) a search for additonal activities previously overlooked, including protein kinase activity, 7) investigations of possible involvement of the enzyme in mediated cellular and intracellular (nuclear) glucose transport, and 8) continued attempts to purify the enzyme.